Volumetric induction phase shift detection system for determining tissue water content properties

ABSTRACT

A method and apparatus of determining the condition of a bulk tissue sample, by: positioning a bulk tissue sample between a pair of induction coils (or antennae); passing a spectrum of alternating current (or voltage) through a first of the induction coils (or antennae); measuring spectrum of alternating current (or voltage) produced in the second of the induction coils (or antennae); and comparing the phase shift between the spectrum of alternating currents (or voltages) in the first and second induction coils (or antennae), thereby determining the condition of the bulk tissue sample.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a Continuation and claims priority to a U.S.patent application Ser. No. 14/805,057, filed Jul. 21, 2015 which is acontinuation of U.S. patent application Ser. No. 14/507,492, filed Oct.6, 2014 (now abandoned) which is a continuation of U.S. patentapplication Ser. No. 14/109,647, filed Dec. 17, 2013 (now abandoned);which is a continuation of U.S. patent application Ser. No. 13/723,696,filed on Dec. 21, 2012 (now U.S. Pat. No. 8,633,033); which is acontinuation of U.S. patent application Ser. No. 13/329,080, filed Dec.16, 2011 (now U.S. Pat. No. 8,361,391); which is a Continuation of U.S.patent application Ser. No. 13/028,082, filed on Feb. 15, 2011 (now U.S.Pat. No. 8,101,421); which is a Continuation of U.S. patent applicationSer. No. 12/616,102, filed on Nov. 10, 2009 (now U.S. Pat. No.7,910,374); which is a Continuation of U.S. patent application Ser. No.11/664,755, filed on Feb. 25, 2008 (now U.S. Pat. No. 7,638,341); whichis a 371 National Phase patent application of PCT application serialnumber PCT/US2006/18384, filed on May 12, 2006; which claims the benefitof Provisional patent application Ser. No. 60/689,401, filed on Jun. 9,2005, the disclosures of which are hereby incorporated herein byreference in their entirety.

GOVERNMENT SUPPORT

This invention was made with government support under Grant No. RR018961awarded by the National Institutes of Health. The government has certainrights in the invention.

TECHNICAL FIELD

The present invention relates to non-contact systems for assessing watercontent properties in bulk tissue, and identifying medical conditionsassociated with abnormal tissue water content properties.

BACKGROUND OF THE INVENTION (a) Medical Conditions Caused by AbnormalTissue Water Content:

A variety of different medical conditions are associated with abnormaltissue water content. Examples of such medical conditions include, butare not limited to: edema (including brain edema), ischemia, internalbleeding (including intraperitoneal bleeding), dehydration, andextravasation.

A change in water content occurring in an organ or a tissue sample overtime can be very indicative of a medical condition developing. As willbe explained below, different systems have been developed to assesstissue water content properties (and changes in such conditions overtime). Such systems can be particularly useful in diagnosing the onsetof various medical conditions. However, as will be shown, existingsystems all suffer from various disadvantages.

(b) Edema and Ischemia:

Tissue edema is a pathological condition involving an increase in theamount of fluid in tissue. The accumulation of fluid can beextracellular, intracellular or both. Extracellular edema is causedeither by increased ultrafiltration or decrease in reabsorption.Intracellular edema can be caused by ischemia and the resultingintracellular hyperosmolarity or as a consequence of extracellularhypotonicity. Independent of the edema type, the condition is one inwhich the amount of liquid in the tissue increases and the balance ischanged, usually as a function of time after an event has occurred.Tissue edema is of substantial concern when it occurs in the brain or inthe lung. In the brain, extracellular edema develops in a delayedfashion, over a period of hours or days, after a large hemisphericstroke and is a cause of substantial mortality. Ischemic brain edemabegins with an increase in tissue Na+ and water content and continueswith blood brain barrier breakdown and infarction of both the parenchymaand the vasculature itself.

A study of the Center for Disease Control and Prevention for the periodfrom 1995 to 2001 indicates that at least 1.4 million annual traumaticbrain injuries occur in the USA alone. These resulted in about 1.1million emergency department visits, 235,000 hospitalizations and about50,000 deaths. About 1,100 incidents per 100,000 in population occur inthe age group from 0 to 4 years. Head injury causes more deaths anddisability than any other neurological condition under the age of 50 andoccurs in more than 70% of accidents. It is the leading cause of deathin males under 35 yr old. Fatalities may not result from the immediateinjury; rather, progressive damage to brain tissue develops over time.In response to trauma, changes occur in the brain that requiresmonitoring to prevent further damage.

Brain swelling can be caused by an increase in the amount of blood tothe brain. Brain edema is one of the most important factors leading tomorbidity and mortality in brain tumors. Cerebral edema, which is anincrease in brain volume caused by an absolute increase in tissue watercontent, ensues. The accumulation of fluid can be extracellular,intracellular or both. Vasogenic edema results from trans-vascularleakage often caused by the mechanical failure of the tight endothelialjunction of the blood-brain barrier and increased ultrafiltration ordecrease in re-absorption. Vasogenic edema also results fromextravasation of protein rich filtrate in interstitial space andaccumulation of extracellular fluid. Cytotoxic edema is characterized bycell swelling. Cytotoxic edema is an intracellular process resultingfrom membrane ionic pump failure. It is very common after head injuryand it is often associated with post-traumatic ischemia and tissuehypoxia. The primary mechanism is reduction of sodium-potassium ATPasepump efficiency due to local hypoxia and ischemia. This type of edemaoccurs in cancer with compression of microcirculation. Interstitial orhydrocephalic edema occurs when there is an accumulation ofextracellular fluid in the setting of hydrocephalus. Intraventriculartumors or tumors that constrict ventricles can cause this type of edema.

Independent of the edema type, the condition is one in which the amountof liquid in the tissue increases or the balance is changed. Edema is ofsubstantial concern when it occurs in the brain. The characteristics ofbrain edema, is that it develops in a delayed fashion, over a period ofhours or days, after the brain trauma has occurred and is a cause ofsubstantial mortality. Detection and continuous monitoring of edema inthe brain is essential for assessment of medical condition andtreatment.

Pulmonary edema is often associated with lung injury and also requirescontinuous monitoring and treatment. Detection and continuous monitoringof edema in the brain and lung is useful for assessment of medicalcondition and treatment.

Ischemia of tissues and organs is caused by a change in normativephysiological conditions such as deprivation of oxygen and blood flow.It can occur inside the body, for instance as a consequence ofimpediments in blood flow. Ischemia also can occur outside the body whenorgans preserved for transplantation are transported. Ischemia resultsin changes in the intracellular composition which is accommodated bychanges in the water content properties of the intracellular andextracellular space and leads to cell death.

Therefore, in medical applications it is important to be able to detectchanges in water content properties which are indicative of theoccurrence of edema and ischemia.

(c) Internal and Interperitoneal Bleeding:

Trauma is the third most common cause of death in all age groups and theleading cause of death in the first three decades of life. Of alltraumatic injuries abdominal and pelvic injuries contribute to about 20%of the fatalities. In addition, death from abdominal hemorrhage is acommon cause of preventable death in trauma patients. Bleeding is thecause of one in four maternal deaths worldwide. Death may occur in lessthan two hours after the onset of bleeding associated with childbirth.In addition to trauma, abdominal bleeding also occurs in severalpost-surgery conditions. Unfortunately, early intraperitoneal bleedingcannot be detected by vital signs (rate pulse or blood pressure) and itbecomes evident only after a critical amount of blood has found its wayinto the abdominal cavity. Therefore, death from abdominal hemorrhage isa common cause of preventable death in trauma patients. However, earlydetection of intraperitoneal bleeding may play a critical role in thepatient survival.

(d) Extravasation:

Extravasation is the unwanted passage or escape of blood, serum, lymphor therapeutic drugs directly into body tissues. Signs and symptoms mayinclude the sudden onset of localized pain at an injection site, suddenredness or extreme pallor at an injection site, or loss of blood returnin an intravenous needle. Extravasation can lead to skin and tissuenecrosis, and “Compartment Syndrome” (a pathologic condition caused bythe progressive development of arterial compression and reduction ofblood supply).

Similar to the medical conditions described above, extravasation resultsin a change in water content properties in the tissue (typically at ornear an injection site). Thus, it would be desirable to detectextravasation, (preferably by a on-contact system). Unfortunately, nosuch system currently exists.

(e) Existing Systems for Assessing Tissue Water Content Properties—andtheir Limitations:

Accumulation of fluid in tissue changes the electrical impedance of thetissue. This has suggested the use of bioelectrical impedancemeasurements to detect water content in the body since 1962. Edema andischemia can be also detected with bioelectric measurements. With edemaor ischemia, the ratio between extracellular and intracellular waterchanges. Since this should cause a shift in the beta dispersionfrequency, bioimpedance spectroscopy based on measuring the changes inthe overall impedance has been viewed as a likely way to produceinformation on edema and ischemia.

Another important method to evaluate and monitor edema is ElectricalImpedance Tomography (EIT). EIT uses an array of electrodes (placed onthe patient) to inject subsensory currents and measure the resultantvoltages. The data is used to reconstruct a map of the electricalimpedance of tissue. Unfortunately, a problem with electrical impedancetomography (EIT) is that it requires the placement of needles in contactwith the tissue. Furthermore, EIT produces an image of the area showingthe location of the change in water content properties. This is a timeconsuming process. In addition the details produced by imaging may notbe needed in many applications of detection of water content properties.

Another way to detect edema and ischemia is by performing inductiontomography. In this approach, induction currents rather than injectioncurrents are used to produce a map of the electrical properties oftissue. The problem with this method is that the induction coils need tobe large, i.e. are much larger than electrodes, and there aredifficulties with using large number of coils for good imagingresolution. Furthermore the imaging outcome has the same overallattributes as EIT in regards to detection of edema and ischemia. Ingeneral, imaging and tomography are expensive and require manymeasurements. In the past, direct impedance measurements of ischemiahave been used to assess the condition of organs preserved fortransplantation. However as with EIT, this requires the placement ofneedles on the organ or tissue. This is cumbersome with organs andimpossible in such tissues as the brain and the lungs or large volumesof the abdomen.

Tumor associated edema is visible on both CT and MRI. Unfortunately, thediagnostic is complicated by the fact that on CT it produces low signal,which can be confused with low-signal producing tumors. On MRI, theedematous brain produces a hypersignal, which may be confused withhypersignal producing tumors.

With regard to diagnosing abdominal injuries, there are two methods forrapid detection of intraperitoneal bleeding, FAST (focused assessmentwith sonography for trauma) ultrasound and peritoneal lavage.Evaluations of the practice in the evaluation of internal injuries showthat physicians prefer to use FAST ultrasound over diagnostic peritoneallavage (DPL) because DPL is invasive and most doctors have limitedexperience in DPL and interpreting the results. However, rural hospitalsrarely have advanced imaging modalities such as CT scan or emergencyultrasound. As a result, emergency physicians in such centers are forcedto rely on clinical examination and plain radiography alone. The lack ofadvanced imaging may delay the identification of patients who requiretransfer, or lead to inappropriate transfer of patients who are laterfound not to require trauma centre intervention.

In addition, most of the current bioelectronic techniques for detectionof abdominal bleedings try to produce an image or information that willdetermine the site of bleeding. However, currently in the medicalemergency departments initial evaluation and treatment is not gearedtowards identification of a specific abdominal injury, but rather todetermine if one exists.

SUMMARY OF THE INVENTION

The present invention provides an electrical measurement system thatconveniently produces bulk information on the properties of organ ortissue. In preferred aspects, the present invention uses bioimpedanceanalysis based on the conduction of an applied electrical current in thetissue to detect a variety of medical conditions.

In one aspect of the invention, the present system provides anon-contact method for detecting tissue properties in a volume of tissueby measuring change in electromagnetic induction spectroscopicdistribution of phase shift over time. Thus, instantaneous bulkmeasurements of the electrical properties of an organ or tissue samplecan be made with induction currents. In another aspect of the invention,the present system provides a non-contact method for detecting changesin tissue properties in a volume of tissue by measuring change inelectromagnetic induction spectroscopic distribution of phase shift overa period of time.

In either of the above instantaneous “snapshot” aspect approach, or themeasurement of changes occurring over time approach, measurements aremade detecting phase shift between the applied and measured currents.Specifically, a change is detected in the phase angle between the ACcurrents in an emitting and a sensing induction coil or antenna. Thisphase shift is caused by a volume of tissue placed between the emittingand a sensing coil or antenna through which AC currents are passed overa wide range (i.e.: spectrum) of frequencies.

As will be shown below, the present invention provides a spectroscopicmeasuring method that is simpler and more reliable than overallimpedance measurement. In addition, the present invention provides asystem of measuring the electromagnetic change in water contentproperties in the bulk would suffice for many applications.

The present invention can thus be use to evaluate the medical conditionof a volume of biological tissue by assessing the bulk tissue electricalproperties of the volume of tissue, and determining how they change overtime.

There are numerous advantages to the present invention, including, butnot limited to, the following:

First, the present invention does not require galvanic coupling betweenthe electrode and the skin or the tissue under measurement. Instead, thepresent system is completely non-invasive. As a result, it is easy tooperate. Moreover, it is inexpensive to build and to operate. Thus, thepresent invention can be operated in locations and conditions such asremote villages, traffic accidents or military engagement in which thereis no full medical service.

Second, measuring change in phase shift in the bulk of tissue, body ororgan with time is a simple measurement that focuses only on theoccurrence of changes in a particular frequency or range of frequencies.Thus, the present system of bulk detection has the advantage of low costand ease of use while still providing relevant data.

Third, a further advantage of the present system is that instantaneousmeasurement of the phase shift can be made. Alternately, however, timedependent measurements can also be made to detect the progress of thephase shift in time to determine the development of the medicalcondition

Fourth, the present invention is especially well suited to detect edemain the brain since the skull does not represent a barrier for theelectromagnetic field at certain frequencies.

Fifth, while imaging the body or the organ may be of importance, veryoften in clinical practice it is sufficient simply to know that there isa problem occurring (and to alert the physician to the occurrence).I.E.: to determine that there is edema (or bleeding, or otherconditions) in a certain organ or parts of the body; such as the brainthe abdomen or the lung or that extravasation or dehydration are takingplace. Furthermore, there are many applications in which it issufficient to have a general estimate of the occurrence of ischemia andnot the precise location of the ischemic tissue. For instance, in organtransplantation it is important to know that the organ is functional ornot and not the degree of functionality of the different parts of theorgan. Accordingly, the present system of bulk measurement indicationsof the occurrence of edema or ischemia may be sufficient for manyclinical many applications.

In one aspect, the present invention provides a method of determiningthe condition of a bulk tissue sample, by: positioning a bulk tissuesample between a pair of induction coils or antenna; passing a spectrumof alternating current through a first of the induction coils; measuringspectrum of alternating current produced in the second of the inductioncoils; and comparing the phase shift between the spectrum of alternatingcurrents in the first and second induction coils, thereby determiningthe condition of the bulk tissue sample.

In another aspect of the method, the present invention comparing thephase shift between the spectrum of alternating currents in the firstand second induction coils over time, thereby determining a change inthe condition of the bulk tissue sample over time.

In another aspect, the present invention provides an apparatus fordetermining the condition of a bulk tissue sample, comprising: a firstinduction coil; a second induction coil; an alternating current powersupply connected to the first induction coil, the alternating currentpower supply configured to generate a spectrum of currents in the firstinduction coil; and a measurement system connected to the secondinduction coil, wherein the measurement system is configured to measurea phase shift difference in the spectrum of currents or voltages betweenthe first and second induction coils when the first and second inductioncoils are positioned in relation to each other and of a tissue sample ororgan or body parts.

In another aspect, the present invention provides an apparatus fordetermining the condition of the bulk tissue sample, comprising: a firstantenna; a second antenna; a high frequency electromagnetic waves supplyto generate a spectrum of electromagnetic waves in the first antenna;and a measurement system connected to the second antenna, wherein themeasurement system is configured to measure a phase shift difference inthe spectrum of currents or voltages between the first and secondinduction antennae when the first and second induction antenna arepositioned in relation to each other and of a tissue sample or organ orbody parts.

The present invention has been experimentally validated to show that itcan detect ischemia and/or edema and/or intraperitoneal bleeding.

The present system can be used on a wide variety of tissues, including,but not limited to brain tissue, lung tissue, heart tissue, muscletissue, skin tissue, kidney tissue, cornea tissue, liver tissue, abdomentissue, head tissue, leg tissue, arm tissue, pelvis tissue, chest tissueor trunk tissue.

In some aspects of the invention, the frequency range of the alternatingcurrent is from 10 kHz to 10 GHz. In one aspect, a more preferred rangeis from 1 MHz to 10 GHz. The present invention can be used with coils orantenna. One preferred range for use with coils is from 10 kHz to 1 GHz,with a more preferred range being from 10 kHz to 300 MHz. One preferredrange for use with antennae is from 100 MHz to 10 GHz, with a morepreferred range being from 300 MHz to 10 GHz.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a simplified schematic of the present invention, showing atissue sample positioned between a pair of induction coils.

FIGS. 2A, 2B and 2C show calculated bulk electrical parameters as afunction of frequency for various ratios of normal tissue to edema.

FIG. 3 is a schematic of a device for electro-magnetic field generation.

FIG. 4 is a multi-frequency inductive phase shift detection spectrometerin accordance with the present invention.

FIG. 5 is a calculated graph of phase shift vs. frequency in asimulation of intraperitoneal bleeding.

FIG. 6 is a magnified view of FIG. 5 in the frequency region from 1 to 9MHz.

FIG. 7 is experimentally measured homogenized absolute values of theinductive phase shift as a function of frequency for various tissuevolumes of saline injected into a rat abdomen. The percentage indicatesthe amount of saline injected relative to the total body weight of therat. The rats used in this experiment were about 250 to 300 grin weight.

FIG. 8 is a calculated phase shift in brain tissue with various degreesof edema.

FIGS. 9A and 9B are an experimentally measured phase shift in braintissue in vitro with various degrees of edema.

DETAILED DESCRIPTION OF THE DRAWINGS (a) Theory:

As stated above, the present system assesses tissue condition bydetermining volumetric bulk properties of the water content of thetissue. Specifically, the sensing of an induction phase shift is used toassess tissue condition.

Biological tissues contain compounds with measurable electricalproperties such as the intracellular and extracellular ionic solutions,the capacitative cell membrane, charged macromolecules and polar water.The combination of these compounds in terms of composition and structureaffect the overall electromagnetic properties of the tissue. Theparticular effect of each one of these components and combinations isaffected in a different way as a function of the electromagnetic fieldexcitation frequency and magnitude applied on the tissue. Typicalspectroscopic behavior of certain tissues is illustrated in the 100%blood, brain, muscle and lung curves in FIG. 2 (the other curves in thefigure will be discussed later). The overall effect of excitationfrequency on the electromagnetic properties is well understood since thepioneering work of Schwan (Schwan, H. P. (1957). “Electrical propertiesof tissue and cell suspensions.” Adv. Biol. Med. Phys. 5: 147-209.)Reviews can be can be found in many texts on the topic: S. Grimnes andO. G. Martinsen, Bioimpedance and Bioelectricity Basics. San Diego,Calif.: Academic Press, 2000, pp. 87-124; K. R. Foster and H. P. Schwan,“Dielectric properties of tissues” in Biological Effects ofElectromagnetic Fields. Boca Raton, Fla.: CRC Press, 1996, pp. 27-106.Briefly, body tissues contain intra and extracellular fluids that behaveas electrical conductors and cell membranes that act as electricalcapacitors. At DC and low frequencies electrical current passes mainlythrough the extracellular fluid; at higher frequencies, however, currentpenetrates both intra and extracellular fluids. Therefore, body fluidsand electrolytes are responsible for electrical resistance and cellmembranes for reactance. At MHz frequencies the impedance of proteinsbecomes important and at GHz frequencies the behavior of water issampled. In particular, up to roughly about 100 MHz the behavior shouldbe affected by Maxwell Wagner relaxation of membranes, proteins in waterand bound water whereas above about 100 MHz it should depend on therelaxation of free water, ionic conductivity and bound water. Theincrease in conductivity in the tissue as a function of the GHzfrequency arises from the rotational relaxation of the water dipoles intissue. In this sense, at higher frequencies the observations depend onthe net water content in a volume rather than the cellular structure.

The relation between water and tissue content and properties and complexelectromagnetic properties occurs throughout the frequency domain.Accordingly, the present system can be used to detect changes in tissuewater properties with phase shift in a broad range of frequencies fromkHz to GHz. Since the measurement of interest is phase shift in the bulkof tissue or organs there are several considerations in choosing theappropriate frequency and apparatus involving the significance of whatis measured and the dimensions that can be measured. Since the interestis in phase shift DC type of measurements are not of interest for thistype of measurement. Theoretically it is anticipated that in thefrequency range from about 100 kHz to 1 GHz, depending on the type oftissue, the phase shift measurement will be affected by both therelative distribution between the intracellular water and theextracellular water and the relative amount of water. Therefore thisrange would be useful in detecting such conditions as ischemia, edema,bleeding, extravasation, dehydration. The effects of change in watercontent between the intracellular and extracellular would be mostpronounced between 1 MHz and 400 MHz, with the most sensitivemeasurements between 1 and 100 MHz. Phase shift measured at the higherfrequency range from about 300 MHz to 10 GHz would be most sensitive towater content and would be sensitive to detect edema, bleeding anddehydration. In particular the range of 1 GHz to 10 MHz would be mostsensitive to water content. However, in addition to the sensitivity ofvarious tissues to frequencies, which are tissue and conditiondependent, since the method involves measurement in the bulk of tissueorgans and the body the penetration depth of the various electromagneticwave frequencies is of importance. For instance the penetration depth ofmicrowave frequency energy at between 1 GHz to 3 GHz is about 2 to 10 cmfor soft tissue. Therefore the particular application of the measurementwould relate the integration depth with the measurement frequencies.

(b) Simplified Representation of the Invention:

The present invention deals with a method and an apparatus for detectingphase shift due to tissue water properties in the bulk of tissue. Themethod and the apparatus require an emitter of electromagnetic waves anda receiver to be placed in relation to the bulk tissue to be analyzed.When working in the frequency domain electromagnetic coils are used foremitters and receivers in the frequency range of up to 400 MHz. Beyondabout 400 MHz to several GHz range, antennae (such as microwaveantennae) may be used. In the range of frequencies from about 300 MHz to1 GHz, both coils and antennae could be used.

FIG. 1 is a simplified schematic of the present invention, as follows.

System 10 consists of two induction coils 12 and 14 with the organ orthe part of the body (sample S) to be analyzed placed in a determinedrelation to the coils. It is to be understood that coils 12 and 14 canbe replaced with antennae when operating at higher frequencies.Reference herein is made to coils, However, the present invention is notso limited as antennae can be used instead. Coil 12 is driven by an ACcurrent power supply (not shown) while the current in the other coil 14is produced by induction and measured. The properties of the material(sample S) between coils 12 and 14 determine the currents in theinduction current coil 14. By comparing the voltages in first coil 12 tothose in second coil 14, a measure of the bulk electrical properties ofthe tissue (sample S) there between can be made. In preferredembodiments, the present invention measures the difference in the phasebetween the two AC voltages, i.e. the “phase shift”. In alternateaspects of the invention, a spectrum of voltages is passed through coil12, and a current phase shift is measured in coil 14.

(c) Mathematical Model:

Different mathematical models are used to describe the system of thisinvention. The various mathematical models depend on the frequencyanalyzed. In the frequency range of up to about 1 GHz, more rigorouslyup to 300 MHz a quasi-static assumption can be made. In this range asolution such as that by (Griffiths, Steward et. al., Magnetic InductionTomography-A Measuring System for Biological Materials” Ann. NY Acad.Sci. 873:335-345) can be used for analyzing the phase shift due thewater content properties of tissue. In frequencies above that range thewave propagation becomes important and the eddy currents are notconstant and an analysis of the type described in the same book but onpage 327 is applied.

(i) Theoretical Considerations:

The analysis here follows Griffiths and his colleagues (See: Griffiths,Steward et. al., Magnetic Induction Tomography-A Measuring System forBiological Materials” Ann. NY Acad. Sci. 873:335-345). We consider as asimple case study tissue sample S to be a circular disk of tissue ofradius Rand thickness t, placed centrally and midway between a smallexcitation coil and a small sensing coil spaced at a distance 2a (SeeFIG. 1). The thickness t, was considered to be much less than 2a. Asinusoidal current, of angular frequency ω, flows in excitation coil 12and induces a magnetic field B. The circular nonmagnetic tissue sample Shas conductivity σ and relative permittivity ∈_(r) (it is assumed thatthe skin depth is greater than, t, and therefore the attenuationproduced by the disk is neglected).

Our bulk model of edema assumes that the edema is uniformly distributedin the tissue and that the occurrence of edema will cause the bulkelectrical parameters of the combined tissue to change according to theformula:

$\begin{matrix}\begin{matrix}{{\sigma_{c}\left( {T,F} \right)} = \frac{\left\lfloor {\left( {\sigma_{i} \cdot T} \right) + \left( {\sigma_{l} \cdot F} \right)} \right\rfloor}{100}} \\{{ɛ_{r,1}\left( {T,F} \right)} = \frac{\left\lbrack {\left( {ɛ_{r,3} \cdot T} \right) + \left( {ɛ_{r,5} \cdot F} \right)} \right\rbrack}{100}}\end{matrix} & (1)\end{matrix}$

where the subscripts c, t, and f stand for the composite properties, thetissue properties and fluid properties, respectively. The symbols, T,and, F, give the percentage volume of the pure tissue or the pure fluidrespectively. In accordance with experiments performed by the Applicantsin testing present invention, the tissue and fluid data used were takenfrom Gabriel and Lau (See: “The Dielectric Properties of BiologicalTissues: III. Parametric Models for the Dielectric Spectrum of Tissues”Phys. Med. Biol. 41:2271-2293, 1996) and Duck (See: “Physical Propertiesof Tissue”, London, Academic press, 1990, Chapter 6, 167 223.) Inaccordance with experiments performed by the Applicants in testingpresent invention, blood was considered as the edematous fluid for brainand muscle tissues; and human serum was considered for lung tissue.

FIGS. 2A, 2B and 2C show the bulk electrical parameters as a function offrequency for various ratios of normal tissue to edema calculated fromEqs. (1) and the data in Garbriel and Lau, and Duck, supra. FIG. 2Ashows brain tissues, FIG. 2B shows lung tissues and FIG. 2C shows muscletissues. As expected; three typical major dispersion regions areobserved for all the ratios tissue/fluid. For the cases of brain andmuscle tissues the bulk electrical conductivity of all the ratiostissue/fluids have similar values as the frequency approaches 1 GHz.It's evident that at high frequencies the electrical properties ofbrain, muscle and blood become essentially the same. This fact can beattributed to the y dispersion region where the dielectric properties ofthe tissue are dominated by the water content. In contrast; for the caseof lung tissue the bulk electrical parameters of all the ratiostissue/fluids have different values in the whole bandwidth. Thisbehavior can be explained by the different electrical properties of thehuman serum with respect to the lung tissue.

(ii) Phase Shift in Sensing Coil 14:

Considering the thin “tissue” disk model described above, a sinusoidalcurrent of angular frequency ω, flows in excitation coil 12 and inducesa magnetic field B in sensing coil 14. According to Griffiths, supra,the current induced in the “tissue” disk (sample S) placed between theexcitation coil 12 and the sensing coil 14 causes a perturbation AB inthe field of the sensing coil given by:

$\begin{matrix}{{\frac{\Delta \; B}{B} = {\left( {{\omega \; ɛ_{0}ɛ_{r}} - {j\; \sigma}} \right)\left( \frac{{ta}^{3}{\omega\mu}_{a}}{2} \right)\left\{ {\frac{1}{a^{2}} - \frac{a^{2} + {2R^{2}}}{\left( {a^{2} + R^{2}} \right)^{2}}} \right\}}}\;} & (2)\end{matrix}$

where ∈₀ and μ₀ are the permittivity and permeability of free space,respectively. The total magnetic field B+A B in sensing coil 14 isshifted relative to the primary magnetic field B by an angle θ. Themagnetic field and its perturbation can be obtained from the voltagesinduced in the sensing coil, V_(i) and ΔV_(i). ΔB/B can be defined interms of the induced voltage in sensing coil 14, by:

$\begin{matrix}{\frac{\Delta \; B}{B} = \frac{\Delta \; V_{i}}{V_{i}}} & (3)\end{matrix}$

We define a constant k:

$\begin{matrix}{k = {\left( \frac{{ta}^{3}\mu_{o}}{2} \right)\left\{ {\frac{1}{a^{2}} - \frac{a^{2} + {2R^{2}}}{\left( {a^{2} + R^{2}} \right)^{2}}} \right\}}} & (4)\end{matrix}$

Substituting (3) and (4) into (2), the phase of the total inducedvoltage θ(V_(ind)) in sensing coil 14 with respect to the inducedvoltage by the primary magnetic field in coil 14 could be expressed as afunction of frequency and electrical parameters in the “tissue” diskbetween the coils [16], by:

$\begin{matrix}{{\theta \left( V_{ind} \right)} = {{arc}\mspace{11mu} {{tg}\left( \frac{k\; \omega \; \sigma}{{k\; \omega^{2}ɛ_{0}ɛ_{r}} + 1} \right)}}} & (5)\end{matrix}$

(ii) Phase Shift in Excitation Coil 12:

The magnetic field in the present invention can be generated in thedevice as shown in FIG. 3. Specifically, an oscillator supplies anexcitation signal (V_(exc)) through an output impedance, Z_(out). Thereference voltage (V_(ref)) measured in the excitation coil is given byexpression (6) where Z_(L) is the impedance of a coil composite made ofthe resistance R_(L) and the inductance X_(L), in series.

$\begin{matrix}{V_{ref} = {V_{exc}\left( \frac{Z_{L}}{Z_{out} + Z_{L}} \right)}} & (6)\end{matrix}$

According to Hart L. et al. (See: A noninvasive electromagneticconductivity sensor for biomedical applications” IEEE Trans Biomed Eng32(12): 1011-1022, 1988), the presence of a conductive sample (the“tissue” disk between the coils) causes a change in the impedance of theexcitation coil given by ΔZ_(L)=ΔR_(L)+ΔX_(L), where: ΔR_(L) is theincrease in the coil resistance and ΔX_(L) is the increase in the coilinductance. The expressions for ΔR_(L) and ΔX_(L) were derived in Hartet. al., supra as:

ΔR=32π³*10⁻¹⁴ N ² f ² R′ ³ I′Δσ  (7)

ΔX=64π⁴*10⁻¹⁴ N ² f ² R′ ³ I′∈ ₀Δ∈_(r)  (8)

where: f=ω/2π is the frequency of the excitation signal, N is the numberof coil turns, R′ is the coil radius, ∈₀ is the permittivity of freespace, and ∈_(r) and a are the relative permittivity and electricalconductivity of the “tissue” disk sample respectively. The term I′ is apositive definite constant determined for a specific geometry andseveral approximations are given in Hart et. al., supra. In this studysubstitutions of σ_(c)→Δσ and ∈_(r,c)→Δ∈_(r) were made for theexpressions (7) and (8) because changes in electrical conductivity andrelative permittivity of the “tissue” sample are considered.

The phase of the reference voltage θ(V_(ref)) with respect to theexcitation signal in the presence of a “tissue” sample can be estimatedfrom the following expression:

$\begin{matrix}{{\theta \left( V_{ref} \right)} = {{arc}\mspace{11mu} {{ig}\left\lbrack {{{Im}\left\lbrack \frac{Z_{2} + {\Delta \; Z_{L}}}{Z_{out} + Z_{1} + {\Delta \; Z_{ɛ}}} \right\rbrack}/{{Re}\left\lbrack \frac{Z_{L} + {\Delta \; Z_{L}}}{Z_{\omega} + Z_{ɛ} + {\Delta \; Z_{L}}} \right\rbrack}} \right\rbrack}}} & (9)\end{matrix}$

Later in this study, the analysis for estimation of phase shift withedema was performed by using tissue properties from the experimentaldata in Gabriel and Duck, supra, and from the solution of equation (5)and (9) with the bulk properties from equation (1). The total change inphase shift (Δθ) between the reference and induced voltages in theexcitation and sensing coil respectively is given by the expression:

Δθ=θ(V _(ind))−θ(V _(ref))  (10)

(d) Experimental System:

FIG. 4 illustrates a multi-frequency inductive spectrometer system 10 asdesigned, constructed and operated by the Applicants. This system ispreferably used for a frequency of up to 400 MHz. System 10 comprisesfour modules: function generator 20, transceiver 30, dual-channeldemodulator 40 and analog digital converter 50. A personal computer 60with a Pentium 2 GHz processor (model 4400, Dell Inc. Round Rock, Tex.)controls the system and processes the data.

Function generator 20 uses two identical programmable synthesizers 22and 24 (NI 5401, National Instruments Inc, Austin, Tex.) as oscillators.Oscillator 22 supplies an excitation signal I cos(ω_(e)t) ofapproximately 20 mA in the range of 1 to 8 MHz at pre-programmed steps.A modulation signal I cos(ω_(m)t) is generated by second oscillator 24.The difference ω_(e)−ω_(m)=ω_(o)=100(2π) rad/sec is maintained constantin the whole bandwidth in order to produce a narrow band measuredvoltage signal on a constant low intermediate frequency for processingand demodulation, as proposed by Ristic, B. et al. (See: “Development ofan impredance spectrometer for tissue monitoring: application ofsynchronous sampling principle” Proc 21st IEEE Annual NortheastConference, 22-23 May 1995, pages 74-75).

The excitation and modulation signals are connected to transceiver 30and dual-channel demodulator 40 modules respectively. Transceiver 30consists of an excitation coil 12 and a sensing coil 14 coaxiallycentered at a distance d=10 cm and two differential receiver amplifiers32 and 34 (AD8130, Analog Devices Inc. Norwood, Mass.). Both coils 12and 14 were built with magnet wire AWG32 rolled on a cylindrical plasticformer with radius r=2 cm, five turns. The coil inductance, ascalculated on the basis of Faraday's law, is approximately 40 pH. Theexcitation coil 12 generates a primary oscillating magnetic field. Thesensing coil 14 detects the primary magnetic field and its perturbationthrough a proximal conductive tissue sample S. To avoid inductive pickupthe leads of the coils are twisted. The amplifiers 32 and 34 wereconnected as conventional operational amplifiers and collect thereference voltage (V_(ref)) and the induced voltage (V_(ind)) in theexcitation 12 and sensing 14 coils respectively. The gain of amplifiers32 and 34 was adjusted in order to obtain a dynamic range of ±5Vthroughout the whole bandwidth.

Dual-channel demodulator 40 uses a pair of mixers 42 and narrow bandpass filters 44 to transfer the information of any excitation andsensing signal of a variable frequency to a constant low frequency(ω_(o)). A multiplier (AD835, Analog Devices Inc. Norwood, Mass.) wasused as mixer 42. Narrow band pass filter 44 was designed on the basisof operational amplifier 32 (AD844, Analog Devices Inc. Norwood, Mass.).This module used two identical channels for parallel demodulation.

To avoid additional inductance and stray capacitance in the circuit,amplifiers 32 and 34 and dual channel-demodulator circuits 40 wereshielded by a metallic box and connected to coils 12 and 14 with shortcoaxial cables (length less than 0.8 m). The current passes through theshield to minimize any inductance mutual between the circuit and thecoils.

Analog-digital conversion module 50 digitized the reference and inducedvoltage signals on the constant low frequency. A data acquisition cardNI 6071E (National Instruments Inc, Austin, Tex.) with a sample rate of1.25 MSamples/seg and a resolution of 12 bits was used as analog-digitalconverter 50. The phase of the reference and induced voltages werecalculated in software over approximately five cycles by an extractsingle tone function available in LAB VIEW V 6.1 (National InstrumentsInc, Austin, Tex.). This function was programmed to find the highestamplitude at 100(2π) rad/sec and return the phase. The phase shiftbetween the reference and induced voltage was estimated asΔθ=θ(V_(ind))−θ(V_(ref)). The ratio signal to noise (SNR) for phaseshift measurement was improved by averaging over twenty spectra (39 dBat 1 MHz).

For use up to higher frequencies including GHz range the presentapparatus may comprise of a source of electromagnetic energy such as anRF Signal generator (Agilent 8648D9 KHz-4 GHz. The source is connectedto an emitter which is a single frequency commercial antenna formicrowave or radiofrequency placed in relation to the analyzed tissueand another similar receiving antenna. The receiving antennae isconnected to an amplifier such as (Low Noise Amplifier, Agilent 11909A,9 KHz-1 GHz), or (Microwave system amplifier Agilent 83006A10 MHz-26.5GHz). The signal and the phase shift can be detected with Agilent 4396BRF Network/Spectrum/Impedance Analyzer, 100 kHz to 1.8 GHz).

(e) Experimental Results—Detection of Interperitoneal Bleeding in Rats:

Intraperitoneal bleeding in the abdomen of a rat was simulated byinfusion of various volumes of physiological saline into the abdominalcavity in rats. Specifically, experiments were performed identically oneach of five rats. The experiments started with anesthetization of theanimal via intraperitoneal injection of Nembutal solution (50 mg/mlsodium pentobarbital, Abbot Labs, North Chicago, Ill.) for a total of100 mg sodium pentobarbital per kg of rat. To simulate intraperitonealbleeding and accumulation of fluids in the abdomen we injected variousvolumes of physiological saline (0.9% w/w NaCl) into the abdominalcavity through a short intravenous catheter (Venflow). The catheterremained in place throughout the experiment. We injected increasingvolumes of saline and the measurements were done for four volumes of: 1,2.5, 5 and 7.5% of (weight of saline)/(weight of the tested rat). Thephysiological saline was maintained at approximately 36.5° C. prior toinjection. In all the experiments the baseline reference measurement wasfor the experimental subject prior to the intraperitoneal physiologicalsaline injection. In all the experiments the coils were placed aroundthe abdomen of the rat in such a way that the abdominal cavity wascentered between the excitation and sensing coils. The geometricalposition was carefully maintained as similar as possible for all thesubjects.

The Applicants studied the phase shift due to four different volumes ofsaline in the frequency range from 1 MHz to 8.5 MHz with an inductionsystem for measuring bulk phase shift. As will be shown below, the testresults show that inductive bulk measurements of phase shift aresensitive to the relative volume of saline at frequencies higher thanapproximately 1 MHz, which is qualitatively consistent with ourtheoretical predications. In addition, the phase shift detectedincreases as a function of frequency and the fluid volume alsoqualitatively consistent with the theoretical predictions. As such, theresults indicate that bulk induction measurement of the phase shift hasthe potential for becoming a robust means for non-contact detection ofintraperitoneal bleeding.

FIG. 5 is a calculated graph of phase shift vs. frequency. FIG. 5 wasobtained from our theoretical calculation for gut tissue and shows theabsolute homogenized values of the inductive phase shift as a functionof frequency for various volumes of physiological saline into theabdominal cavity, simulating various degrees of bleeding. The resultsare shown in a homogenized form with respect to the values withoutsaline. As can be seen, an increase in the volume of injected salinecauses an increase in inductive phase shift. Specifically, the relativephase shift caused by internal bleeding begins at about 1 MHz. The phaseshift difference due to internal bleeding has a characteristic inverse Utype shape with a maximal at about 1000 MHz. The behavior shown in thefigure beyond 1 GHz is highly approximate.

As can be seen, the values of the phase shift obtained from theanalytical calculations provide an excellent qualitative indication ofthe effect of internal bleeding. Thus, the present system operates evenif the bulk properties of the tissue in the abdomen are substantiallydifferent from the values that we used, since we did not consider fat,muscle, food and many other components in the abdomen. Nevertheless, theresults suggest that the resolution of the measurement is greater forcertain optimal values. In optional clinical applications, the phaseshift can be scanned over a wide range of values to determine the bestfrequency for the highest signal to noise measurement.

The results in FIG. 5 indicate that the phase shift due to internalbleeding should be detectable from about 1 MHz. FIG. 6 is a magnifiedview of the phase shift in FIG. 5 in the frequency region from 1 to 9MHz, which confirms this. Here it is important to notice that in thisrange the phase shift relative to baseline increases with an increase inmeasurement frequency and amount of simulated internal bleeding. We havechosen this range of frequencies for our experimental studies because itis the onset of the phenomenon of phase shift due to internal edema.

FIG. 7 shows the experimentally measured homogenized absolute values ofthe inductive phase shift as a function of frequency for various volumesof physiological saline into the abdominal cavity, simulating variousdegrees of bleeding. The results are shown in a homogenized form withrespect to the control values, the baseline measurements. In this modeof presentation, the experimental subject without water produces zerophase shift at all frequencies and the injection of the physiologicalsaline solution produces the departure from zero. Another advantage ofpresenting the results homogenized with respect to the control values isto overcome possible bias in the electronic circuitry. The frequency isgiven in a logarithmic scale from 1 to 8.5 MHz. The value of onestandard error is also shown in the figure. The beating of the heart,breathing as well as abdominal motion might change the bulk electricalproperties of the composite body under measurement. These factors mayaffect the magnitude and phase of the induced voltage at the sensingcoil in the whole bandwidth. To remove natural artifacts due tophysiological activity, 20 measurements were taken at each frequency.Averaging over these measurements has the effect of a robust filter tophysiological activity artifacts. The figure shows that the change inphase shift due to simulated internal bleeding begins at about 1 MHz andincreases with frequency and amount of internal bleeding. Qualitatively,the experimental results are very similar to the theoreticalcalculations.

In summary: these experimental results confirm that measuring therelative spectroscopic distribution of induction phase shift in the bulkof the abdominal cavity can be used for non-contact detection ofintraperitoneal bleeding. Thus, in clinical practice, induction phaseshift can be measured as a function of time and frequency in patientswho are in danger of internal bleeding.

(f) Experimental Results—Detection of Brain Edema:

As will be shown herein, our results verified that bulk measurement ofinductive phase shift can be used for non-contact detection of thecontent of water in brain, lung and muscle tissue. The analyticalresults of FIG. 2 showed an increase of the phase shift proportional tothe water content starting at frequencies as low as 10 MHz. In addition,our results show that the phase shift changes with frequency, in arather complex manner.

The results show that the phase shift is sensitive to the relativevolume of edema at frequencies higher than approximately 10 MHz. Theeffect of edema on brain, lung and muscle tissues is tissue typespecific. Increasing the volume of tissue has the effect of lowering thefrequency at which the phase shift becomes sensitive to the volume ofedema. The results indicate that bulk induction measurement of the phaseshift has the potential for becoming a simple means for non-contactdetection of formation of edema in brain, lung and muscle tissues.

As a first order model of edema in the brain, ex-vivo brain tissue ofpig (used approximately 8 hours after the animal sacrifice) wasprocessed through a mixer and combined with various volumes of aphysiological saline solution (0.9% w/w NaCl) to form a homogeneouspaste. In accordance with experiments performed by the Applicants intesting present invention, the brain conductivity data used in therelevant calculations were taken from Gabriel's experimental report forexcised bovine brain tissue supra. The data for excised bovine braintissue was obtained two hours postmortem and at body temperature. Thefluid was taken as a solution of 0.9% w/w of NaCl, with a constantelectrical conductivity σ=1.3 S/m and a relative permittivity ∈_(r)=80.

In our preparation, the changes in the electrical properties of braintissue with the increase in water content may be explained as thedilution of a mixture of water and the proteins present in dried tissue.In the analyzed frequency range the cellular membranes have lowimpedance, and the tissue may be treated as a suspension of proteins inwater. The significance of this is that, in the brain, at frequencies atthe high end of the beta dispersion and above our experimental modelwill be comparable to that in viable tissue. At frequencies at the lowend of the beta dispersion a greater difference between live tissue andedematous fluid is seen, and therefore, in that range, the effect ofedema is more pronounced than determined in our experiment. Therefore,the present experimental model could be considered to provide a lowerlimit in the sensitivity of edema detection with our techniques and wecan anticipate that the detection will be even better in a livingorganism.

Three different volume ratios between the volume of brain tissue and ofsaline were evaluated: 10, 20 and 30%. The paste was placed in acylindrical and nonmagnetic recipient made of Teflon with a radius R=7.5cm and height t=8 cm. This volume was chosen because it is on the orderof a typical adult brain volume. In addition we studied samples of purebrain tissue that was also homogenized and pure physiological saline.

A calculation of the penetration depth (δ) as a function of frequencyfor saline and brain tissue was done according to the expression:

δ=(2/ωμ₀σ)^(1/2)

where μ₀ is the permeability of free space. We used the electricalconductivity data reported in Gabriel, supra for excised bovine braintissue. The data for excised bovine brain tissue was obtained two hourspost-mortem and at body temperature. The fluid was taken as a solutionof 0.9% w/w of NaCl, with a constant electrical conductivity σ=1.3 S/mand a relative permittivity ∈_(r)=80. The result shows that at 10 MHz;the skin depth is around 14 and 30 cm for pure saline and brainrespectively. These values are larger than the thickness of the sample(8 cm).

All the samples were geometrical and vertically centered betweenexcitation coil 12 and sensing coil 14. The geometrical position wascarefully maintained as similar as possible for all the samples.

For every sample, twenty spectra of phase shift were obtained in therange of from 1 to 8 MHz. The data were averaged over twenty separatemeasurements, for each frequency. To overcome the bias in the phaseshift due to the system electronics, the data were homogenized withrespect to the values for brain 100%. In this way the changes observedin phase will depend essentially only on the electrical properties ofthe sample. The measurements were made at the room temperature(approximately 24° C.).

FIGS. 8 and 9 show the difference between the calculated (FIG. 8) ormeasured (FIG. 9) phase shift in brain tissue with various degrees ofedema and the calculated or measured phase shift in the case with 100%brain tissue, as a function of frequency. In this mode of presentationbrain tissue without edema produces zero phase shift at all frequenciesand the addition of saline produces the departure from zero. FIG. 8shows the calculated inductive phase shift as a function of frequencyfor various ratios of normal brain tissue to physiological saline,simulating various degrees of edema. The calculations were made bysolving Eq. (10) and inserting in Eq. (1) brain tissue properties takenfrom Gabriel, supra. The edematous fluid was taken as saline (NaCl, 0.9%w/w) with a constant electrical conductivity σ=1.3 S/m and a relativepermittivity ∈_(r)=80. FIG. 8 shows the calculated phase shift as afunction of frequency in the range of from 1 MHz to 1000 MHz. Theanalytical study shows that the phase shift is changing with frequencyin a U shaped form and appears to have a maximum at about 100 MHz.Evidently, the phase shift increases with saline content, at anyfrequency. FIG. 8 shows that the phase shift can be used to measureedema in a wide range of frequencies and that there may be some optimalvalues of frequency that produce the highest signal.

The outcome of our experiments is shown in FIG. 9A, which shows thephase shift of various compositions of brain tissue and saline as afunction of frequency. Specifically, FIG. 9A shows the phase shift fromthree different volume ratios between the volumes of saline to braintissue: 10, 20 and 30%. Data for 100% saline is also shown. FIG. 9Bshows the part of the curve developed in FIG. 8 in the range of theexperimental measurements, to 8 MHz. A comparison of FIGS. 9A and 9Bshows that the experimental results are quantitatively and qualitativelysimilar to the theoretical predictions. The phase shift increases withfrequency and with water content. The frequency is given in alogarithmic scale from 1 to 8 MHz. The value of one standard error isalso shown in the figure. The error in our experimental apparatusincreases with an increase in frequency for all the volume ratios ofsaline to brain tissue.

The data in FIGS. 8 and 9 are presented by homogenizing the measuredphase shift with respect to the phase shift in the case with 100% braintissue. Therefore, the difference between the calculated or measuredphase shift in brain tissue with various degrees of edema and thecalculated or measured phase shift in the case with 100% brain tissue isshown as a function of frequency.

In this mode of presentation, brain tissue without edema produces zerophase shift at all frequencies and the addition of saline produces thedeparture from zero. With this mode of presentation, the sensitivity ofour method for detecting edema by measuring bulk phase shift becomesclear, as does the effect of measurement frequency. Another advantage ofpresenting the results homogenized with respect to 100% brain tissuephase shift is to overcome possible bias in the electronic circuitry.Furthermore, this homogenized mode of presentation removes any systemicerrors that could be caused by the electronics circuitry producing abias in the experimentally measured phase shift.

A further advantage of the present system is that in the analyzedfrequency domain phase shift is a measure that is strongly dependent onwater content in relation to organic molecular cellular contents and noton cell structure.

It is clear from FIGS. 8 and 9 that phase shift due to changes in watercontent is substantial and detectable. In FIGS. 8 and 9, the departurefrom zero is the indication for change in water content. The change inphase shift increases with frequency and with water content. Theexperimental results suggest that the capability of the measurementsystem to detect water content improves at high frequencies. Forexample, the phase shift value detected at 8 MHz is clearly larger forall the tested samples.

Our results also show that measurable differences in phase shift arenoted between 3 MHz to 4 MHz with higher volumes of saline producingmeasurable phase differences at lower frequencies. Our resultsdemonstrate that valuable information for detection of phase shift withedema can be obtained at frequencies that are three orders of magnitudelower than the microwave frequencies and in a broad range offrequencies. The curve of saline alone provides the upper limit of theexpected phase shift measurement relative to pure brain tissue.

The present invention can thus be used to continuously monitor phaseshift to detect worsening conditions of increase in edematous fluid inthe brain. Specifically, continuously measuring the relative changes inphase shift with time would produce curves as shown in FIG. 9 in thecase of formation of edema. Thus, detecting changes in phase shift couldpoint to worsening conditions of the patient.

Extending the present study over a wider range of frequencies may alsohold much information since our analytical studies predicts a non-linearbehavior throughout the range from MHz to GHz.

In summary, the results of this theoretical and in vitro study providesubstantive preliminary information, which suggests that measuring therelative spectroscopic distribution of induction phase shift can producea robust means for noncontact detection of occurrence of edema in thebrain.

1. A method of determining the condition of a bulk tissue sample,comprising: positioning a bulk tissue sample between a pair of inductioncoils or antennae; passing a spectrum of alternating current or voltagethrough a first of the induction coils or antennae; measuring a spectrumof alternating current or voltage produced in the second of theinduction coils or antennae; and comparing the phase shift between thespectrum of alternating currents or voltages in the first and secondinduction coils or antennae, thereby determining the condition of thebulk tissue sample.
 2. The method of claim 1, wherein the first andsecond induction coils or antennae do not contact the bulk tissuesample.
 3. The method of claim 1, wherein determining the condition ofthe bulk tissue sample comprises: detecting at least one condition fromthe group consisting of edema, ischemia, bleeding, dehydration, wateraccumulation in the bulk tissue sample, extravasation, and disease. 4.The method of claim 1, wherein the bulk tissue sample is selected fromthe group consisting of brain tissue, lung tissue, heart tissue, muscletissue, skin tissue, kidney tissue, cornea tissue, liver tissue, abdomentissue, head tissue, leg tissue, arm tissue, pelvis tissue, chest tissueor trunk tissue.
 5. The method of claim 1, wherein the frequency of thespectrum of alternating current is between 10 kHz and 10 GHz.
 6. Themethod of claim 1, wherein the frequency of the spectrum of alternatingcurrent is between 1 MHz and 10 GHz.
 7. The method of claim 1, whereindetermining the condition of the bulk tissue sample comprises detectingedema, ischemia, dehydration, extravasation, in the tissue sample, andwherein the spectrum of frequency of the alternating current is between100 kHz to 10 GHz.
 8. The method of claim 1, wherein determining thecondition of the bulk tissue sample comprises detecting interperitonealbleeding in the tissue sample, and wherein the spectrum of frequency ofthe alternating current is between 100 kHz to 10 GHz
 9. A method ofdetermining changes in the condition of a bulk tissue sample over time,comprising: positioning a bulk tissue sample between a pair of inductioncoils or antennae; passing a spectrum of alternating current or voltagethrough a first of the induction coils or antennae; measuring a spectrumof alternating current or voltage produced in the second of theinduction coils or antennae; and comparing the phase shift between thespectrum of alternating currents or voltages in the first and secondinduction coils or antennae over time, thereby determining a change inthe condition of the bulk tissue sample over time.
 10. The method ofclaim 9, wherein the first and second induction coils or antennae do notcontact the bulk tissue sample.
 11. The method of claim 9, whereindetermining the change in the condition of the bulk tissue sample overtime comprises: detecting a change over time in at least one conditionfrom the group consisting of edema, ischemia, bleeding, dehydration,water accumulation in the bulk tissue sample, extravasation, anddisease.
 12. The method of claim 9, wherein the bulk tissue sample isselected from the group consisting of brain tissue, lung tissue, hearttissue, muscle tissue, skin tissue, kidney tissue, cornea tissue, livertissue, abdomen tissue, head tissue, leg tissue, arm tissue, pelvistissue, chest tissue or trunk tissue.
 13. An apparatus for determiningthe condition of a bulk tissue sample, comprising: a first inductioncoil or antenna; a second induction coil or antenna; an alternatingcurrent power supply connected to the first induction coil or antenna,the alternating current power supply configured to generate a spectrumof currents or voltages in the first induction coil or antenna; and ameasurement system connected to the second induction coil or antenna,wherein the measurement system is configured to measure a phase shiftdifference in the spectrum of currents or voltages between the first andsecond induction coils or antennae when the first and second inductioncoils or antennae are positioned on opposite sides of a tissue sample.14. The apparatus of claim 13, further comprising: a system to comparethe phase shift between the alternating currents or voltages in thefirst and second induction coils or antennae to determine the conditionof the bulk tissue sample.
 15. The apparatus of claim 13, wherein thealternating current power supply produces a spectrum of alternatingcurrents with a frequency between 10 kHz and 10 GHz.
 16. The apparatusof claim 13, wherein the alternating current power supply produces aspectrum of alternating currents with a frequency between 1 MHz and 10GHz.
 17. The apparatus of claim 14, wherein the system to determine thecondition of the bulk tissue sample comprises: a system configured todetect at least one of edema, ischemia, bleeding, dehydration, wateraccumulation in the bulk tissue sample, extravasation, and disease byanalysis of the phase shift difference in the currents between the pairof induction coils or antennae.
 18. The apparatus of claim 13, whereinthe alternating current power supply comprises: a function generatorconfigured to generate an alternating current in the first inductioncoil or antenna having a frequency that changes in pre-programmed steps.19. The apparatus of claim 18, wherein the function generator suppliesan excitation signal of approximately 20 mA in the range of 1 to 8.5 MHzat pre-programmed steps.
 20. The apparatus of claim 13, furthercomprising: a first differential receiving amplifier connected to thefirst induction coil or antenna; and a second differential receivingamplifier connected to the second induction coil or antenna.
 21. Theapparatus of claim 13, further comprising: a dual-channel demodulatorconnected to the first and second induction coils or antennae; and ananalog-digital converter connected to the dual-channel demodulator. 22.The apparatus of claim 21, wherein the dual-channel demodulatorcomprises: a mixer; and a narrow band pass filter.